Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy
Abstract Background Drug combinations of the proteasome inhibitor bortezomib with cytotoxic chemotherapy are currently evaluated in phase 2 and 3 trials for the treatment of paediatric acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL). Methods We investigated whether expression rat...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2016-09-01
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| Series: | Journal of Hematology & Oncology |
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| Online Access: | http://link.springer.com/article/10.1186/s13045-016-0312-z |
| _version_ | 1818482409164767232 |
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| author | Denise Niewerth Gertjan J. L. Kaspers Gerrit Jansen Johan van Meerloo Sonja Zweegman Gaye Jenkins James A. Whitlock Stephen P. Hunger Xiaomin Lu Todd A. Alonzo Peter M. van de Ven Terzah M. Horton Jacqueline Cloos |
| author_facet | Denise Niewerth Gertjan J. L. Kaspers Gerrit Jansen Johan van Meerloo Sonja Zweegman Gaye Jenkins James A. Whitlock Stephen P. Hunger Xiaomin Lu Todd A. Alonzo Peter M. van de Ven Terzah M. Horton Jacqueline Cloos |
| author_sort | Denise Niewerth |
| collection | DOAJ |
| description | Abstract Background Drug combinations of the proteasome inhibitor bortezomib with cytotoxic chemotherapy are currently evaluated in phase 2 and 3 trials for the treatment of paediatric acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL). Methods We investigated whether expression ratios of immunoproteasome to constitutive proteasome in leukaemic cells correlated with response to bortezomib-containing re-induction chemotherapy in patients with relapsed and refractory acute leukaemia, enrolled in two Children’s Oncology Group phase 2 trials of bortezomib for ALL (COG-AALL07P1) and AML (COG-AAML07P1). Expression of proteasome subunits was examined in 72 patient samples (ALL n = 60, AML n = 12) obtained before start of therapy. Statistical significance between groups was determined by Mann-Whitney U test. Results Ratios of immunoproteasome to constitutive proteasome subunit expression were significantly higher in pre-B ALL cells than in AML cells for both β5i/β5 and β1i/β1 subunits (p = 0.004 and p < 0.001). These ratios correlated with therapy response in AML patients; β1i/β1 ratios were significantly higher (p = 0.028) between patients who did (n = 4) and did not reach complete remission (CR) (n = 8), although for β5i/β5 ratios, this did not reach significance. For ALL patients, the subunit ratios were also higher for patients who showed a good early response to therapy but this relation was not statistically significant. Overall, for this study, the patients were treated with combination therapy, so response was not only attributed to proteasome inhibition. Moreover, the leukaemic blast cells were not purified for these samples. Conclusions These first ex vivo results encourage further studies into relative proteasome subunit expression to improve proteasome inhibition-containing therapy and as a potential indicator of bortezomib response in acute leukaemia. |
| first_indexed | 2024-12-10T11:47:28Z |
| format | Article |
| id | doaj.art-172eb78a2bea491c981a5e1211f1352f |
| institution | Directory Open Access Journal |
| issn | 1756-8722 |
| language | English |
| last_indexed | 2024-12-10T11:47:28Z |
| publishDate | 2016-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Hematology & Oncology |
| spelling | doaj.art-172eb78a2bea491c981a5e1211f1352f2022-12-22T01:50:01ZengBMCJournal of Hematology & Oncology1756-87222016-09-01911910.1186/s13045-016-0312-zProteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapyDenise Niewerth0Gertjan J. L. Kaspers1Gerrit Jansen2Johan van Meerloo3Sonja Zweegman4Gaye Jenkins5James A. Whitlock6Stephen P. Hunger7Xiaomin Lu8Todd A. Alonzo9Peter M. van de Ven10Terzah M. Horton11Jacqueline Cloos12Department of Pediatric Oncology/Hematology, VU University Medical CenterDepartment of Pediatric Oncology/Hematology, VU University Medical CenterDepartment of Amsterdam Rheumatology & Immunology Center, VU University Medical CenterDepartment of Pediatric Oncology/Hematology, VU University Medical CenterDepartment of Hematology, VU University Medical CenterDepartment of Pediatrics, Texas Children’s Cancer and Hematology Centers, Baylor College of MedicineDepartment of Pediatrics, Hospital for Sick Children, University of TorontoDepartment of Pediatrics, University of Colorado Health Sciences CenterCOG Operations OfficeDepartment of Preventive Medicine, University of Southern CaliforniaDepartment of Epidemiology and Biostatistics, VU University Medical CenterDepartment of Pediatrics, Texas Children’s Cancer and Hematology Centers, Baylor College of MedicineDepartment of Pediatric Oncology/Hematology, VU University Medical CenterAbstract Background Drug combinations of the proteasome inhibitor bortezomib with cytotoxic chemotherapy are currently evaluated in phase 2 and 3 trials for the treatment of paediatric acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL). Methods We investigated whether expression ratios of immunoproteasome to constitutive proteasome in leukaemic cells correlated with response to bortezomib-containing re-induction chemotherapy in patients with relapsed and refractory acute leukaemia, enrolled in two Children’s Oncology Group phase 2 trials of bortezomib for ALL (COG-AALL07P1) and AML (COG-AAML07P1). Expression of proteasome subunits was examined in 72 patient samples (ALL n = 60, AML n = 12) obtained before start of therapy. Statistical significance between groups was determined by Mann-Whitney U test. Results Ratios of immunoproteasome to constitutive proteasome subunit expression were significantly higher in pre-B ALL cells than in AML cells for both β5i/β5 and β1i/β1 subunits (p = 0.004 and p < 0.001). These ratios correlated with therapy response in AML patients; β1i/β1 ratios were significantly higher (p = 0.028) between patients who did (n = 4) and did not reach complete remission (CR) (n = 8), although for β5i/β5 ratios, this did not reach significance. For ALL patients, the subunit ratios were also higher for patients who showed a good early response to therapy but this relation was not statistically significant. Overall, for this study, the patients were treated with combination therapy, so response was not only attributed to proteasome inhibition. Moreover, the leukaemic blast cells were not purified for these samples. Conclusions These first ex vivo results encourage further studies into relative proteasome subunit expression to improve proteasome inhibition-containing therapy and as a potential indicator of bortezomib response in acute leukaemia.http://link.springer.com/article/10.1186/s13045-016-0312-zPediatric acute leukaemiaBortezomibProteasome inhibitorImmunoproteasome |
| spellingShingle | Denise Niewerth Gertjan J. L. Kaspers Gerrit Jansen Johan van Meerloo Sonja Zweegman Gaye Jenkins James A. Whitlock Stephen P. Hunger Xiaomin Lu Todd A. Alonzo Peter M. van de Ven Terzah M. Horton Jacqueline Cloos Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy Journal of Hematology & Oncology Pediatric acute leukaemia Bortezomib Proteasome inhibitor Immunoproteasome |
| title | Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy |
| title_full | Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy |
| title_fullStr | Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy |
| title_full_unstemmed | Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy |
| title_short | Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy |
| title_sort | proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib containing chemotherapy |
| topic | Pediatric acute leukaemia Bortezomib Proteasome inhibitor Immunoproteasome |
| url | http://link.springer.com/article/10.1186/s13045-016-0312-z |
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